Prognostic Value of HIF-1α-Induced Genes in Sepsis/Septic Shock.

Hypoxia is characterized as one of the main consequences of sepsis, which is recognized as the leading cause of death in intensive care unit (ICU) patients. In this study, we aimed to examine whether the expression levels of genes regulated under hypoxia could be utilized as novel biomarkers for sepsis prognosis in ICU patients. Whole blood expression levels of hypoxia-inducible factor-1α (HIF1A), interferon-stimulated gene 15 (ISG15), hexokinase 2 (HK2), lactate dehydrogenase (LDHA), heme oxygenase-1 (HMOX1), erythropoietin (EPO), and the vascular endothelial growth factor A (VEGFA) were measured on ICU admission in 46 critically ill, initially non-septic patients. The patients were subsequently divided into two groups, based on the development of sepsis and septic shock (n = 25) or lack thereof (n = 21). HMOX1 mRNA expression was increased in patients who developed sepsis/septic shock compared to the non-septic group (p < 0.0001). The ROC curve, multivariate logistic regression, and Kaplan-Meier analysis demonstrated that HMOX1 expression could be utilized for sepsis and septic shock development probability. Overall, our results indicate that HMOX1 mRNA levels have the potential to be a valuable predictive factor for the prognosis of sepsis and septic shock in ICU patients.

Investigation of Serum Endocan Levels and Age in Critical Inflammatory Conditions.

Aging negatively affects the endothelium. Endocan (ESM-1), an endothelium-derived soluble proteoglycan, participates in fundamental biological processes of endothelial cells. We aimed to examine the role of endothelial dysfunction and age in poor outcomes in critical illness. ESM-1 levels were measured in the sera of mechanically ventilated critically ill patients, including COVID-19, non-septic, and septic patients. The 3 patient cohorts were divided based on age (≥65 and <65). Critically ill COVID-19 patients had statistically higher ESM-1 levels compared to critically ill septic and non-septic patients. Only in critically ill septic patients were ESM-1 levels higher in older compared to younger patients. Finally, the age-subgrouped patients were further subdivided based on intensive care unit (ICU) outcome. ESM-1 levels were similar in COVID-19 survivors and non-survivors, irrespective of age. Interestingly, only for the younger critically ill septic patients, non-survivors had higher ESM-1 levels compared to survivors. In the non-septic survivors and non-survivors, ESM-1 levels remained unaltered in the younger patients and tended to be higher in the elderly. Even though endocan has been recognized as an important prognostic biomarker in critically ill patients with sepsis, in our patient cohort, increased age, as well as the extent of endothelial dysfunction, seemed to affect its prognostic ability.

Epidemiology of Mucormycosis in Greece; Results from a Nationwide Prospective Survey and Published Case Reports.

Mucormycosis has emerged as a group of severe infections mainly in immunocompromised patients. We analysed the epidemiology of mucormycosis in Greece in a multicentre, nationwide prospective survey of patients of all ages, during 2005-2022. A total of 108 cases were recorded. The annual incidence declined after 2009 and appeared stable thereafter, at 0.54 cases/million population. The most common forms were rhinocerebral (51.8%), cutaneous (32.4%), and pulmonary (11.1%). Main underlying conditions were haematologic malignancy/neutropenia (29.9%), haematopoietic stem cell transplantation (4.7%), diabetes mellitus (DM) (15.9%), other immunodeficiencies (23.4%), while 22.4% of cases involved immunocompetent individuals with cutaneous/soft-tissue infections after motor vehicle accident, surgical/iatrogenic trauma, burns, and injuries associated with natural disasters. Additionally, DM or steroid-induced DM was reported as a comorbidity in 21.5% of cases with various main conditions. Rhizopus (mostly R. arrhizus) predominated (67.1%), followed by Lichtheimia (8.5%) and Mucor (6.1%). Antifungal treatment consisted mainly of liposomal amphotericin B (86.3%), median dose 7 mg/kg/day, range 3-10 mg/kg/day, with or without posaconazole. Crude mortality was 62.8% during 2005-2008 but decreased significantly after 2009, at 34.9% (p = 0.02), with four times fewer haematological cases, fewer iatrogenic infections, and fewer cases with advanced rhinocerebral form. The increased DM prevalence should alert clinicians for timely diagnosis of mucormycosis in this patient population.

Association Between Vaccination Status and Mortality Among Intubated Patients With COVID-19-Related Acute Respiratory Distress Syndrome.

Importance: Although vaccination substantially reduces the risk of severe COVID-19, it is yet unknown whether vaccinated patients who develop COVID-19 and require invasive mechanical ventilation have lower mortality than controls. Objective: To examine the association between COVID-19 vaccination status and mortality among critically ill patients who require invasive mechanical ventilation owing to acute respiratory distress syndrome (ARDS) related to COVID-19. Design, Setting, and Participants: This multicenter cohort study was performed between June 7, 2021, and February 1, 2022, among 265 consecutive adult patients with COVID-19 in academic intensive care units who underwent invasive mechanical ventilation owing to ARDS. Exposures: Patients in the full vaccination group had completed the primary COVID-19 vaccination series more than 14 days but less than 5 months prior to intubation. This time threshold was chosen because guidelines from the US Centers for Disease Control and Prevention recommend a booster dose beyond that time. The remaining patients (ie, those who were unvaccinated, partially vaccinated, or fully vaccinated <14 days or >5 months before intubation) comprised the control group. Main Outcomes and Measures: The primary outcome was time from intubation to all-cause intensive care unit mortality. A Cox proportional hazards regression model including vaccination status, age, comorbid conditions, and baseline Sequential Organ Failure Assessment score on the day of intubation was used. Results: A total of 265 intubated patients (170 men [64.2%]; median age, 66.0 years [IQR, 58.0-76.0 years]; 26 [9.8%] in the full vaccination group) were included in the study. A total of 20 patients (76.9%) in the full vaccination group received the BNT162b2 vaccine, and the remaining 6 (23.1%) received the ChAdOx1 nCoV-19 vaccine. Patients in the full vaccination group were older (median age, 72.5 years [IQR, 62.8-80.0 years] vs 66.0 years [IQR, 57.0-75.0 years]) and more likely to have comorbid conditions (24 of 26 [92.3%] vs 160 of 239 [66.9%]), including malignant neoplasm (6 of 26 [23.1%] vs 18 of 239 [7.5%]), than those in the control group. Full vaccination status was significantly associated with lower mortality compared with controls (16 of 26 patients [61.5%] died in the full vaccination group vs 163 of 239 [68.2%] in the control group; hazard ratio, 0.55 [95% CI, 0.32-0.94]; P = .03). Conclusions and Relevance: In this cohort study, full vaccination status was associated with lower mortality compared with controls, which suggests that vaccination might be beneficial even among patients who were intubated owing to COVID-19-related ARDS. These results may inform discussions with families about prognosis.

Autotaxin Has a Negative Role in Systemic Inflammation.

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.

Comparison of the Mortality Prediction Value of Soluble Urokinase Plasminogen Activator Receptor (suPAR) in COVID-19 and Sepsis.

In the last years, biomarkers of infection, such as the soluble urokinase plasminogen activator receptor (suPAR), have been extensively studied as potential diagnostic and prognostic biomarkers in the intensive care unit (ICU). In this study, we investigated whether this biomarker can be used in COVID-19 and non-COVID-19 septic patients for mortality prediction. Serum suPAR levels were measured in 79 non-COVID-19 critically ill patients upon sepsis (within 6 h), and on admission in 95 COVID-19 patients (66 critical and 29 moderate/severe). The non-COVID-19 septic patients were matched for age, sex, and disease severity, while the site of infection was the respiratory system. On admission, COVID-19 patients presented with higher suPAR levels, compared to non-COVID-19 septic patients (p < 0.01). More importantly, suPAR measured upon sepsis could not differentiate survivors from non-survivors (p > 0.05), as opposed to suPAR measured on admission in COVID-19 survivors and non-survivors (p < 0.0001). By the generated ROC curve, the prognostic value of suPAR in COVID-19 was 0.81, at a cut-off value of 6.3 ng/mL (p < 0.0001). suPAR measured early (within 24 h) after hospital admission seems like a specific and sensitive mortality risk predictor in COVID-19 patients. On the contrary, suPAR measured at sepsis diagnosis in non-COVID-19 critically ill patients, does not seem to be a prognostic factor of mortality.

COVID-19 Disease and Outcomes among Critically Ill Patients: The Case of Medical Nutritional Therapy.

The recent COVID-19 pandemic, which resulted from SARS CoV-2 coronavirus infection, contributed toa rapid increasein hospital and intensive care unit (ICU) admissions [...].

Rapidly improving acute respiratory distress syndrome in COVID-19: a multi-centre observational study.

BACKGROUND: Before the pandemic of coronavirus disease (COVID-19), rapidly improving acute respiratory distress syndrome (ARDS), mostly defined by early extubation, had been recognized as an increasingly prevalent subphenotype (making up 15-24% of all ARDS cases), associated with good prognosis (10% mortality in ARDSNet trials). We attempted to determine the prevalence and prognosis of rapidly improving ARDS and of persistent severe ARDS related to COVID-19. METHODS: We included consecutive patients with COVID-19 receiving invasive mechanical ventilation in three intensive care units (ICU) during the second pandemic wave in Greece. We defined rapidly improving ARDS as extubation or a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) greater than 300 on the first day following intubation. We defined persistent severe ARDS as PaO2:FiO2 of equal to or less than 100 on the second day following intubation. RESULTS: A total of 280 intubated patients met criteria of ARDS with a median PaO2:FiO2 of 125.0 (interquartile range 93.0-161.0) on day of intubation, and overall ICU-mortality of 52.5% (ranging from 24.3 to 66.9% across the three participating sites). Prevalence of rapidly improving ARDS was 3.9% (11 of 280 patients); no extubation occurred on the first day following intubation. ICU-mortality of patients with rapidly improving ARDS was 54.5%. This low prevalence and high mortality rate of rapidly improving ARDS were consistent across participating sites. Prevalence of persistent severe ARDS was 12.1% and corresponding mortality was 82.4%. CONCLUSIONS: Rapidly improving ARDS was not prevalent and was not associated with good prognosis among patients with COVID-19. This is starkly different from what has been previously reported for patients with ARDS not related to COVID-19. Our results on both rapidly improving ARDS and persistent severe ARDS may contribute to our understanding of trajectory of ARDS and its association with prognosis in patients with COVID-19.

Prognostic Value of Bone Formation and Resorption Proteins in Heterotopic Ossification in Critically-Ill Patients. a Single-Centre Study.

INTRODUCTION: A potential complication in critically ill patients is the formation of bone in soft tissues, termed heterotopic ossification. The exact pathogenetic mechanisms are still undetermined. Bone morphogenetic proteins induce bone formation, while signalling through the receptor activator of nuclear factor kappa-Β (RANK) and its ligand (RANKL), regulates osteoclast formation, activation, and survival in normal bone modelling and remodelling. Osteoprotegerin protects bone from excessive bone loss by blocking RANKL from binding to RANK. AIM: The study aimed to investigate these molecules as potential prognostic biomarkers of heterotopic ossification development in critically ill patients. MATERIALS AND METHODS: In this prospective observational study, BMP-2, RANKL, and osteoprotegerin were measured by ELISA in twenty-eight critically-ill, initially non-septic patients, on admission to an ICU, seven days post-admission, and thirty days after ICU discharge. RESULTS: In the critically-ill cohort, nine of the twenty-eight patients developed heterotopic ossification up to the 30-day follow-up time-point. The patients who developed heterotopic ossification exhibited significantly reduced BMP-2 and RANKL levels on ICU admission, compared to patients who did not; Osteoprotegerin readings were similar in both groups. CONCLUSIONS: Critically-ill patients who will subsequently develop heterotopic ossification, have significantly lower BMP-2 and RANKL levels at the time of ICU admission, suggesting that these proteins may be useful as prognostic markers for this debilitating condition.

Serum Neutrophil Gelatinase-Associated Lipocalin (NGAL) Could Provide Better Accuracy Than Creatinine in Predicting Acute Kidney Injury Development in Critically Ill Patients.

Acute kidney injury (AKI) is one of the most common complications in critically ill patients. In recent years, studies have focused on exploring new biomarkers for the early diagnosis and prognosis of AKI. The aim of this study was to investigate serum prognostic biomarkers (neutrophil gelatinase-associated lipocalin, NGAL, and creatinine) of AKI in critically ill patients. The study included 266 critically ill, initially nonseptic, patients admitted to a multidisciplinary ICU. Serum levels of NGAL and creatinine were measured at ICU admission. ROC curves were generated to estimate the prognostic value of the biomarkers, while a logistic regression analysis was performed to assess their association with an increased AKI risk. Patients were divided in two groups based on the development (n = 98) or not (n = 168) of AKI during their ICU stay. Serum NGAL levels at ICU admission were significantly higher in those who subsequently developed AKI compared to those who did not (p < 0.0001). NGAL was shown to be more accurate in predicting AKI development than creatinine; furthermore, NGAL levels were associated with an increased risk of AKI development (1.005 (1.002-1.008), p < 0.0001). In the present study, we were able to demonstrate that increased serum NGAL levels at ICU admission might be predictive of AKI development during ICU hospitalization. Further studies are needed to support NGAL as a prognostic marker of acute kidney injury.

The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19.

There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection. Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Consequently, mast cell histamine and its receptors represent promising pharmacological targets. At the same time, nutritional modulation of immune system function has been proposed and is being investigated for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy. Several studies indicate that several immunonutrients can regulate mast cell activity to reduce the de novo synthesis and/or release of histamine and other mediators that are considered to mediate, at least in part, the complex pathophysiology present in COVID-19. This review summarizes the effects on mast cell histamine of common immunonutrients that have been investigated for use in COVID-19.

Evaluating the Role of the Interleukin-23/17 Axis in Critically Ill COVID-19 Patients.

Studies have hypothesized a potential role of the interleukin (IL)-23/17 axis in coronavirus disease 2019 (COVID-19). However, to date, levels of IL-23 and 17 have not been compared between critically ill COVID-19 patients and critically ill non-COVID-19 patients. IL-23 and 17 were measured on admission to the intensive care unit (ICU) in critically ill COVID-19 (N = 38) and critically ill non-COVID-19 (N = 34) patients with an equal critical illness severity. Critically ill non-COVID-19 patients did not have sepsis or septic shock on ICU admission. None of the enrolled patients had previously received corticosteroids. In our study, circulating IL-17 levels were higher in the COVID-19 patients. More specifically, critically ill COVID-19 patients had levels of 0.78 (0.05-1.8) pg/mL compared to 0.11 (0.05-0.9) pg/mL in the critically ill non-COVID-19 patients (p = 0.04). In contrast, IL-23 levels were comparable between groups. A group of patients hospitalized in the specialized COVID-19 clinic (N = 16) was also used to evaluate IL-17 and IL-23 levels with respect to COVID-19 severity. Non-critically ill COVID-19 patients had undetectable levels of both cytokines. Our results support the notion of inhibiting IL-17 in critical COVID-19 infection.

Could Soluble Endothelial Protein C Receptor Levels Recognize SARS-CoV2-Positive Patients Requiring Hospitalization?

INTRODUCTION: The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in COVID-19 has not been explored. In this study, we investigated whether sEPCR levels were related to COVID-19 patients' requirement for hospitalization. METHODS: Plasma sEPCR levels were measured on hospital admission in 84 COVID-19 patients, and in 11 non-hospitalized SARS-CoV2-positive patients approximately 6 days after reported manifestation of their symptoms. Multiple logistic regression analysis was performed to identify potential risk factors for hospitalization and receiver operating characteristic (ROC) curves were generated to assess their value. RESULTS: In our cohort, hospitalized patients had considerably higher sEPCR levels upon admission compared with outpatients [107.5 (76.7-156.3) vs. 44.6 (12.1-84.4) ng/mL; P < 0.0001)]. The ROC curve using hospitalization as the classification variable and sEPCR levels as the prognostic variable generated an area under the curve at 0.845 (95% CI = 0.710-0.981, P < 0.001). Additionally, we investigated the predictive value of sEPCR combined with BMI, age, or D-dimers. CONCLUSIONS: In our cohort, sEPCR levels in COVID-19 patients upon hospital admission appear considerably elevated compared with outpatients; this could lead to impaired APC activities and might contribute to the pro-coagulant phenotype reported in such patients. sEPCR measurement might be useful as a point-of-care test in SARS-CoV2-positive patients.

Selection of the Appropriate Control Group Is Essential in Evaluating the Cytokine Storm in COVID-19.

BACKGROUND/AIM: Lately, studies have reported contradicting results on the cytokine storm seen in critically-ill COVID-19 patients. Depending on the control group used, cytokines have been found to be higher, similar or even lower in COVID-19 compared to critical illnesses associated with elevated cytokine concentrations. However, most of these studies do not take into account critical illness severity. Hence, we decided to compare cytokine levels in critically-ill COVID-19 patients and critically-ill patients of a general intensive care unit (ICU), who did not have sepsis or septic shock, but had an equal disease severity. PATIENTS AND METHODS: Interleukin (IL)-6, IL-8, IL-10 and tumour necrosis factor-α (TNF-α) were measured on ICU admission in mechanically ventilated, COVID-19 (N=36) and non-COVID-19 (N=30) patients, who had not received dexamethasone, and had equal critical illness severity. Non-COVID-19 patients did not have sepsis or septic shock. RESULTS: In our case control study, circulating IL-6 and IL-10 were lower, while TNF-α and IL-8 levels were higher in critically-ill COVID-19 patients, compared to critically-ill non-COVID-19 patients. CONCLUSION: It is difficult to infer whether the cytokine storm seen in COVID-19 differs from other critical conditions. It is important to recognize that the conclusions of related studies may depend on control group selection.

Does Route of Full Feeding Affect Outcome among Ventilated Critically Ill COVID-19 Patients: A Prospective Observational Study.

The outbreak of the new coronavirus strain SARS-CoV-2 (COVID-19) highlighted the need for appropriate feeding practices among critically ill patients admitted to the intensive care unit (ICU). This study aimed to describe feeding practices of intubated COVID-19 patients during their second week of hospitalization in the First Department of Critical Care Medicine, Evaggelismos General Hospital, and evaluate potential associations with all cause 30-day mortality, length of hospital stay, and duration of mechanical ventilation. We enrolled adult intubated COVID-19 patients admitted to the ICU between September 2020 and July 2021 and prospectively monitored until their hospital discharge. Of the 162 patients analyzed (52.8% men, 51.6% overweight/obese, mean age 63.2 ± 11.9 years), 27.2% of patients used parenteral nutrition, while the rest were fed enterally. By 30 days, 34.2% of the patients in the parenteral group had died compared to 32.7% of the patients in the enteral group (relative risk (RR) for the group receiving enteral nutrition = 0.97, 95% confidence interval = 0.88-1.06, p = 0.120). Those in the enteral group demonstrated a lower duration of hospital stay (RR = 0.91, 95% CI = 0.85-0.97, p = 0.036) as well as mechanical ventilation support (RR = 0.94, 95% CI = 0.89-0.99, p = 0.043). Enteral feeding during second week of ICU hospitalization may be associated with a shorter duration of hospitalization and stay in mechanical ventilation support among critically ill intubated patients with COVID-19.

Serum Coenzyme Q10 Levels are Decreased in Critically-Ill Septic Patients: Results From a Preliminary Study.

BACKGROUND: The increased oxidative stress resulting from the inflammatory responses in sepsis initiates changes in mitochondrial function which may result in organ damage, the most common cause of death in the intensive care unit (ICU). Deficiency of coenzyme Q10 (CoQ10), a key cofactor in the mitochondrial respiratory chain, could potentially disturb mitochondrial bioenergetics and oxidative stress, and may serve as a biomarker of mitochondrial dysfunction. Hence, we aimed to investigate in initially non-septic patients whether CoQ10 levels are decreased in sepsis and septic shock compared to ICU admission, and to evaluate its associations with severity scores, inflammatory biomarkers, and ICU outcomes. METHODS: Observational retrospective analysis on 86 mechanically-ventilated, initially non-septic, ICU patients. CoQ10 was sequentially measured on ICU admission, sepsis, septic shock or at ICU discharge. CoQ10 was additionally measured in 25 healthy controls. Inflammatory biomarkers were determined at baseline and sepsis. RESULTS: On admission, ICU patients who developed sepsis had lower CoQ10 levels compared to healthy controls (0.89 vs. 1.04 µg/ml, p < 0.05), while at sepsis and septic shock CoQ10 levels decreased further (0.63 µg/ml; p < 0.001 and 0.42 µg/ml; p < 0.0001, respectively, from admission). In ICU patients who did not develop sepsis, admission CoQ10 levels were also lower than healthy subjects (0.81 µg/ml; p < 0.001) and were maintained at the same levels until discharge. CONCLUSION: CoQ10 levels in critically-ill patients are low on ICU admission compared to healthy controls and exhibit a further decrease in sepsis and septic shock. These results suggest that sepsis severity leads to CoQ10 depletion.

Lactate Kinetics Reflect Organ Dysfunction and Are Associated with Adverse Outcomes in Intensive Care Unit Patients with COVID-19 Pneumonia: Preliminary Results from a GREEK Single-Centre Study.

Coronavirus disease-19 (COVID-19) continues to be a health threat worldwide. Increased blood lactate is common in intensive care unit (ICU) patients; however, its association with outcomes in ICU COVID-19 patients remains currently unexplored. In this retrospective, observational study we assessed whether lactate is associated with outcomes in COVID-19 patients. Blood lactate was measured on ICU admission and thereafter daily up to day 14 in 45 patients with confirmed COVID-19 pneumonia. Acute physiology and chronic health evaluation (APACHE II) was calculated on ICU admission, and sequential organ failure assessment (SOFA) score was assessed on admission and every second day. The cohort was divided into survivors and non-survivors based on 28-day ICU mortality (24.4%). Cox regression analysis revealed that maximum lactate on admission was independently related to 28-day ICU mortality with time in the presence of APACHE II (RR = 2.45, p = 0.008). Lactate's area under the curve for detecting 28-day ICU mortality was 0.77 (p = 0.008). Mixed model analysis showed that mean daily lactate levels were higher in non-survivors (p < 0.0001); the model applied on SOFA scores showed a similar time pattern. Thus, initial blood lactate was an independent outcome predictor in COVID-19 ICU patients. The time course of lactate mirrors organ dysfunction and is associated with poor clinical outcomes.

The H3 Haplotype of the EPCR Gene Determines High sEPCR Levels in Critically Ill Septic Patients.

INTRODUCTION: A soluble (s) form of the endothelial protein C receptor (EPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in the septic process is under investigation. This study determined the frequencies of EPCR haplotypes H1 and H3 to investigate possible associations with plasma admission levels of sEPCR in an intensive care unit (ICU) cohort of septic patients. METHODS: Three polymorphisms in the EPCR gene were genotyped in 239 Caucasian critically ill patients, and their plasma sEPCR levels were also measured at the time of admission to the ICU. Multivariate logistic regression analysis controlling for sepsis severity, age, acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores, lactate level, sex, diagnostic category, length of ICU stay and hospital mortality was performed to determine the effect of EPCR haplotypes H1 and H3 on the levels of sEPCR. RESULTS: Individuals carrying at least one H3 allele had significantly higher levels of sEPCR than individuals with no H3 alleles (p < 0.001). No differences were found in the distribution of the H3 allele in the patient groups categorized using the pre-existing and current sepsis-3 definitions. CONCLUSION: Using the preceding and current sepsis definitions, sEPCR levels and the H3 haplotype were not associated with sepsis severity and the risk of poor outcomes in septic patients; however, the EPCR H3 allele contributed to higher levels of sEPCR.

Immune cell response to strenuous resistive breathing: comparison with whole body exercise and the effects of antioxidants.

Background/hypothesis: Whole body exercise (WBE) changes lymphocyte subset percentages in peripheral blood. Resistive breathing, a hallmark of diseases of airway obstruction, is a form of exercise for the inspiratory muscles. Strenuous muscle contractions induce oxidative stress that may mediate immune alterations following exercise. We hypothesized that inspiratory resistive breathing (IRB) alters peripheral blood lymphocyte subsets and that oxidative stress mediates lymphocyte subpopulation alterations following both WBE and IRB. Patients and methods: Six healthy nonathletes performed two WBE and two IRB sessions for 45 minutes at 70% of VO2 maximum and 70% of maximum inspiratory pressure (Pimax), respectively, before and after the administration of antioxidants (vitamins E, A, and C for 75 days, allopurinol for 30 days, and N-acetylcysteine for 3 days). Blood was drawn at baseline, at the end of each session, and 2 hours into recovery. Lymphocyte subsets were determined by flow cytometry. Results: Before antioxidant supplementation at both WBE end and IRB end, the natural killer cell percentage increased, the T helper cell (CD3+ CD4+) percentage was reduced, and the CD4/CD8 ratio was depressed, a response which was abolished by antioxidants only after IRB. Furthermore, at IRB end, antioxidants promoted CD8+ CD38+ and blunted cytotoxic T-cell percentage increase. CD8+ CD45RA+ cell percentage changes were blunted after antioxidant supplementation in both WBE and IRB. Conclusion: We conclude that IRB produces (as WBE) changes in peripheral blood lymphocyte subsets and that oxidative stress is a major stimulus predominantly for IRB-induced lymphocyte subset alterations.

Serum Admission 25-Hydroxyvitamin D Levels and Outcomes in Initially Non-Septic Critically Ill Patients.

INTRODUCTION: To examine whether very low levels of 25-hydroxyvitamin D {25(OH)D} upon admission to the intensive care unit (ICU) are associated with worse outcomes. METHODS: Retrospective observational cohort study of critically ill patients treated in a multidisciplinary ICU. Two hundred twenty seven initially non-septic, critically ill patients, in whom 25-hydroxyvitamin D was measured at ICU admission. An additional group of 192 healthy subjects was also used. Patients were categorized according to their vitamin D levels at admission; the two patient groups were those with severely low 25-hydroxyvitamin D levels (<7 ng/mL, N = 101) and those with vitamin D levels ≥7 ng/mL, N = 126. RESULTS: ICU admission 25-hydroxyvitamin D levels of critically ill patients were much lower than those of healthy subjects (P < 0.0001). The median time to sepsis for the two patient groups did not differ, nor did the length of ICU stay (days). Both groups exhibited similar hospital mortality rates. However, among the fraction of patients who eventually became septic (N = 145), the odds ratio (OR) for developing respiratory infections in patients with admission vitamin levels < 7 ng/mL compared with patients with admission vitamin D levels ≥7 ng/mL was 5.25 {95% confidence interval (CI) 1.5-18.32, P = 0.009}. CONCLUSIONS: Initially non-septic critically ill patients appear to have very low ICU admission 25-hydroxyvitamin D levels. Among critically ill patients, severely low vitamin D levels (<7 ng/mL) at ICU admission do not predict sepsis development, increased risk of in-hospital mortality, or longer stay in the ICU. However, these severely low admission vitamin D levels in patients who will eventually develop sepsis are associated with development of respiratory tract infections.